Abstract
Agents targeting colchicine-binding pocket usually show a minimal drug-resistance issue, albeit often associated with high toxicity. Chalcone-based compounds, which may bind to colchicine-binding site, are found in many edible fruits, suggesting that they can be effective drugs with less toxicity. Therefore, we synthesized and examined 24 quinolone chalcone compounds, from which we identified ((E)-3-(3-(2-Methoxyphenyl)-3-oxoprop-1-enyl) quinolin-2(1H)-one) (CTR-17) and ((E)-6-Methoxy-3-(3-(2-methoxyphenyl)-3-oxoprop-1-enyl) quinolin-2(1H)-one) (CTR-20) as promising leads. In particular, CTR-20 was effective against 65 different cancer cell lines originated from 12 different tissues, largely in a cancer cell-specific manner. We found that both CTR-17 and CTR-20 reversibly bind to the colchicine-binding pocket on β-tubulin. Interestingly however, both the CTRs were highly effective against multidrug-resistant cancer cells while colchicine, paclitaxel and vinblastine were not. Our study with CTR-20 showed that it overcomes multidrug-resistance through its ability to impede MRP1 function while maintaining strong inhibition against microtubule activity. Data from mice engrafted with the MDA-MB-231 triple-negative breast cancer cells showed that both CTR-17 and CTR-20 possess strong anticancer activity, alone or in combination with paclitaxel, without causing any notable side effects. Together, our data demonstrates that both the CTRs can be effective and safe drugs against many different cancers, especially against multidrug-resistant tumors.
Highlights
The microtubule cytoskeleton is a well-validated cancer therapeutic target[1]
Initial screening of the CTR library using three breast cancer cell lines (MCF-7, MDA-MB-468 and MDA-MB-231) and two non-cancer breast cell lines (MCF 10A and 184B5) identified CTR-17 ((E)-3-(3-(2-Methoxyphenyl)-3oxoprop-1-enyl) quinolin-2(1H)-one) and CTR-20 ((E)-6-Methoxy-3-(3-(2-methoxyphenyl)-3-oxoprop-1-enyl) quinolin-2(1H)-one) (Fig. 1a) as promising lead compounds since they effectively and preferentially killed the three cancer cell lines over the two non-cancer cell lines. (The detailed information on the design, synthesis, characterization, and biological effects of the 24 novel chemicals were described in our patent application published recently [WO 2017/083979, 2017], and will be reported in an appropriate scientific journal in near future)
Data obtained from our subsequent works showed that both CTR-17 and CTR-20 effectively killed a wide range of different cancer cell lines including cancers originated from cervix, lung, bladder, kidney, brain, multiple myeloma, lymphoma and breast, at IC50 values from 0.12 μmol/L (MDA-MB-468 by CTR-20) to 1.11 μmol/L (U87MG by CTR-20) (Fig. 1b)
Summary
The microtubule cytoskeleton is a well-validated cancer therapeutic target[1]. There are at least four binding sites on tubulin that can disrupt microtubule dynamics: taxanes, vinca alkaloids, laulimalide and colchicine[2,3,4]. We synthesized and examined 24 novel chalcone-derivatives, among which CTR-17 and CTR-20 (Fig. 1a) were identified as highly promising leads as they effectively and preferentially killed cancer over non-cancer cells. Both the CTR compounds bind to the colchicine binding pocket and cause a prolonged mitotic arrest at the spindle assembly checkpoint (SAC), eventually leading to cell death. Both CTR-17 and CTR-20 effectively killed MDR1- and MRP1-overexpressing tumor cells that showed resistance to colchicine, paclitaxel and other agents. Both CTR-17 and CTR-20 showed strong anti-tumor activity in mice engrafted with metastatic breast cancer cells, without showing any notable side effects
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